Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[CH:50](=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.083 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (981 mg, Example 121), benzaldehyde (434.1 mg) and acetic acid (245.6 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O which caused precipitation of product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to precipitate additional product. The mixture was filtered thru a celite pad. The collected solid was rinsed with water (35 mL×2). The solid was dissolved with EtOAc (50 mL) and then eluted through the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as pink solid (570 mg; 49%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 3H), 7.26 (m, 6H), 7.07 (dd, J=8.0, 8.0 Hz, 1H), 6.60 (m, 2H), 6.54 (s, 1H), 5.04 (s, 1H), 4.50 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.98 (d, J=13.0 Hz, 1H), 3.69 (m, 1H), 3.18 (d, J=13.0 Hz, 1H), 3.02 (m, 2H), 2.70-2.52 (m, 5H), 2.00 (m, 3H), 1.73 (m, 31H), 1.26 (t, J=7.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Ca+2]>CCO.C(Cl)(Cl)Cl>[CH2:8]([O:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#CCCCCNOCc1ccccc1
Yield: 75.4 %

Procedure:
Trifluoroacetic acid (TFA, 16 mL) was added to (B) (2.59 g, 8.51 mmol), and the solution stirred at room temperature for 20 min (Drierite tube). Excess TFA was removed on the rotovap, saturated NaHCO3 (50 mL) was added and the product was extracted into ether (3×50 mL). After a brine wash (50 mL), the organic extracts were concentrated to yield 1.77 g crude product. Column chromatography with 3% EtOH/CHCl3 furnished 1.31 g of (3) (75% yield), which has been previously prepared: NMR δ1.5-1.7 (m, 4 H), 2.16-2.35 (m, 2 H), 2.78-2.98 (m, 2 H), 4.66 (s, 2 H), 5.45 (br s, 1 H), 7.28 (s, 5 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C)c1Cn1cc(N)cn1
Yield: 99 %

Procedure:
Tert-butyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylcarbamate (example 10-41b) (592 mg, 2 mmol) was stirred in a solution of 4N HCl in dioxane (20 mL) at ambient temperature for 2 hours. The solvent was removed and the residue was dissolved in a 1/1 mixture of ethyl acetate/hexanes (30 mL) and concentrated twice. The solid was triturated with hexanes and collected by filtration providing 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (500 mg, 99%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.11 (s, 3H), 2.38 (s, 3H), 5.16 (s, 2H), 7.51 (s, 1H), 8.03 (s, 1H), 10.27 (bs, 3H).
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].CO>[NH2:8][C:9]1[C:18]([F:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Br:20])[CH:10]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)c(NCc2ccccc2)cc1Br
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c(N)cc1Br
Yield: 73.8 %

Procedure:
A suspension of the methyl 4-(benzylamino)-2-bromo-5-fluorobenzoate (2.4 g, 7.10 mmol) in acetic acid was treated with 10% palladium on charcoal (250 mg) and stirred at room temperature under 2 bar hydrogen for 18 hours. The reaction mixture was then diluted with methanol, filtered through celite and evaporated to low volume. The residue was suspended in water (50 mL) and basified with 5% sodium carbonate solution then was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate) and evaporated to a sandy solid. This crude solid was dissolved in the methanol and passed down an SCX cartridge. Evaporation of the methanol eluents gave the title compound (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(SC2CC3CCC(C2)N3)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-chlorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane (8.70 g, 20.28 mmol), 48% HBr (17 mL), and acetic acid (68 mL) was heated to 110° C. for 78 h. The reaction was adjusted to pH 11 by addition of 4 N sodium hydroxide and extracted with methylene chloride. The organic phase was filtered through diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated to afford 3-(4-chlorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a yellow oil. The product was kugelrohr distilled (110-130° C., (pot temperature), 1.5 mm Hg) to give 4.1 g (79%) of 3-(4-chlorophenylsulfanyl)-8-azabicyclo-(3.2.1)-octane as a nearly colorless oil which solidified and had: NMR δ 7.30 (m, 4 H), 3.54 (br t, J=3.5 Hz, 2 H), 3.32 (sym m, 1 H), 1.97-1.72 (m, 5 H), 1.71-1.52 (m, 4 H).
Reaction SMILES: C([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18](=[O:20])[CH3:19])C=CC=CC=1.[C:33]1(C)C=CC=CC=1>>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:8][CH2:9][CH:33]=[CH:17][C:18](=[O:20])[CH3:19]
Reactant: Cc1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C=O)C(=O)OC
Product: COC(=O)CCCC=CC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Methyl formylbutyrate (13 g) and 1-triphenylphosphoranylidene-2-propanone (31.4 g) were refluxed together in toluene (200 ml) for 30 minutes. The toluene was then evaporated off and ether (200 ml) added to the residue to give a suspension which was stirred at room temperature for 5 minutes. The suspended triphenylphosphine oxide was filtered off and washed with a further 100 ml of ether. The combined ether solutions were evaporated to dryness to give a yellow oil which was distilled at 0.1 mm Hg using a Kugelrohr apparatus (air bath temperature 140° C.) to yield 7-oxo-5-octenoic acid methyl ester as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7].[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].[C:25]1(N)[C:30](F)=[C:29](F)[C:28](F)=[C:27]([NH2:34])[C:26]=1F.[ClH:37].Cl>C(Cl)Cl>[Cl:37][C:29]1[CH:28]=[C:27]([N:34]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]34[CH2:17][CH:12]5[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]5)[CH2:9]3)[CH2:15]4)=[O:7])[CH2:18][CH2:19]2)[CH:26]=[CH:25][CH:30]=1.[ClH:37]
Reactant: CCN(CC)CC
Reactant: O=C(OCCCBr)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCCN1CCN(c2cccc(Cl)c2)CC1)C12CC3CC(CC(C3)C1)C2

Procedure:
To a stirred solution of 3-bromopropanol (5.56 g, 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g, 0.02 mol) and triethylamine (4 g, 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight, the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g of the intermediate adamantane-1-carboxylic acid bromopropyl ester. The title compound was prepared by stirring 4-(3-chlorophenyl)-1-piperazine (2.7 g, 0.011 mol), adamantane-1-carboxylic acid bromopropyl ester (3.5 g, 0.011 mol) and triethylamine (2.5 g, 0.025 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf =0.6 in 30% methanol/ethylacetate) was separated and converted to the dihydrochloride salt with ethanolic HCl (1 g, 20% yield), mp. 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of (1-(2,6-dichlorophenyl)-4-isopropyl-1H-1,2,3-triazol-5-yl)methanol (3.0 g, 0.01048 mol) and CBr4 in CH2Cl2 (15 ml) is added a solution of triphenylphosphine (3.50 g, 0.01334 mol) in CH2Cl2 (10 ml) at 0° C. Stir the solution for 4 h at room temperature and concentrate in vacuo to give crude product. Purify by column chromatography over silica gel eluting with 7:3 hexane/ethyl acetate to give 3.0 g (82%) of the title compound. ES/MS m/e (79Br/81Br) 348/350 [M+H]+.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.Cl.[O:20]1[C:24]([CH2:25][S:26][CH2:27][CH2:28]N)=[CH:23][CH:22]=[CH:21]1.[O-]CC.[Na+]>C(O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:24]1[CH2:25][S:26][CH2:27][CH2:28][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: NCCSCc1ccco1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2ccco2)ncc1Cc1cccnc1

Procedure:
(b)(i) 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (12.36 g) was added to a stirred mixture of 2-(5-furylmethylthio)ethylamine hydrochloride (10.65 g) and sodium ethoxide (prepared from 1.26 g sodium) in dry ethanol (300 ml) and the mixture was boiled under reflux for 44 hours and evaporated to dryness. The residue was triturated with water (discarded) and recrystallised from aqueous 2-propanol to give 2-[2-(2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 136°-139°.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12]C)=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.B(Br)(Br)Br>CCOC(C)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]2[C:6]3[CH:10]=[C:11]([OH:12])[C:3]([OH:2])=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:19][CH:18]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: Clc1ccc(CBr)cc1
Agent: BrB(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cc2ncn(Cc3ccc(Cl)cc3)c2cc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dimethoxybenzimidazole (0.100 g, 0.8 mmol) was added 60% NaH (0.021 g, 0.88 mmol). After stirring for 30 min, the 4-chlorobenzylbromide (0.171 g, 0.8 mmol) was added and the solution was heated to 60° C. for 2 h. The reaction solution was diluted with EtOAc (10 mL) and washed with aqueous saturated NaHCO3 (2×10 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. To a solution of the crude alkylated intermediate (0.8 mmol) in CH2Cl2 (10 mL) was added 1 M BBr3 in CH2Cl2 (1 mL, 1 mmol). After stirring for 16 h, the solvent was removed in vacuo and the crude product was purified by reverse-phase preparative HPLC to provide 1-(4-chloro-benzyl)-1H-benzoimidazole-5,6-diol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[O:14])[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[N:6][CH:7]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([N:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)=[O:14])[N:10]=[C:9]2[C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CC(c2ccc(Cl)cn2)C(c2ccc(F)cc2)=N1
Product: CCOC(=O)N(C(=O)N1CC(c2ccc(Cl)cn2)C(c2ccc(F)cc2)=N1)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Sodium hydride (240 mg, 6.00 mmol as a 60 percent slurry in mineral oil) was extracted 3 times with 2 mL portions of dry hexane under an inert atmosphere and then 15 mL of tetrahydrofuran was added and the mixture cooled by stirring in an ice bath. 4-(5-Chloro-2-pyridinyl)-4,5-dihydro-3-(4-fluorophenyl)-N-(4-trifluoromethoxyphenyl)-1H-pyrazole-1-carboxamide (958 mg, 2.00 mmol) was then added in one portion and the mixture allowed to react for 30 min. Ethyl chloro-formate (0.573 mL, 6.00 mmol) was then added with cooling and stirring and the mixture allowed to react at 0°-10° C. for 30 min. The resulting mixture was partitioned between saturated aqueous ammonium chloride and ether. The ethereal phase was dried over magnesium sulfate, and then concentrated by evaporation under reduced pressure. The residue was triturated with 20 mL of ether, refrigerated for about 1 hr, and then recovered by filtration. It was then recrystallized from a mixture of hexane and acetone to obtain 660 mg of the title compound as white crystals melting at 159.5°-161° C. (60 percent yield)
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH:9]([CH3:11])[OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22].[O:27]=O>CN(C)C1C=CN=CC=1.O>[C:22]([O:10][CH:9]([CH3:11])[CH2:8][C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])[CH3:13])(=[O:27])[C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=O
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)OC(C)CC(C)(C)OOC(C)(C)C
Yield: 99 %

Procedure:
A 125 mL Erlenmeyer flask equipped with a magnetic stirring bar was chargedwith 10.0 g (48.4 mmoles) of 92% 3-t-butylperoxy-1,3-dimethylbutanol, 7.8 g(77.2 mmoles) of triethylamine, 0.1 g (0.08 mmole) of 4-dimethylaminopyridine and 30 g of dry ethyl acetate. A clear solution resulted at room temperature. To this vigorously stirred solution at room temperature was slowly added a solution consisting of 7.0 g (50.2 mmoles) of ethyl oxalyl chloride and 10 g of dry ethyl acetate over a period of 20minutes. A precipitate immediately formed and the flask became warm. It wasnecessary to cool the flask in order to maintain the temperature around room temperature. After a total reaction period of 60 minutes, the reaction mass was transferred to a separatory funnel, 100 mL of water was added to the reaction mass and shaken. The aqueous phase was separated anddiscarded. The organic phase was washed once with aqueous 10% HCl solution,twice with water and once with dilute aqueous NaHCO3 solution. The resulting solution was dried over about 10% by weight of anhydrous MgSO4, and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 13.9 g (99% of theory, uncorrected) of a clear yellow liquid. The product contained 5.79% active oxygen (theory, 5.51%), therefore, compound I-1, was obtained with an assay of 100% and in a corrected yield of 99%. Gas chromatographic analysis showed that the product contained less than 0.1% of 3-t-butylperoxy-1,3-dimethylbutanol, the starting material. An infrared (IR) spectrum of the product showed carbonyl bands at 1770 cm-1 and 1745 cm-1 and a peroxide (--OO--) band at 870 cm-1.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39](O)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH2:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1.Cl>CN(C)C=O>[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39]([NH:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1nc(=S)ss1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)Nc2nc(=S)ss2)Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
N-methylmorpholine (0.79 ml, 7.15 mmol), N-hydroxybenzotriazole (1.10 g, 7.15 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.37 g, 7.15 mmol) are added to a solution of 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetic acid (2.00 g, 5.96 mmol) in N,N-dimethylformamide (20 ml) while being cooled with ice, and stirred for 1 hour. Then, the mixture, with 3-amino-1,2,4-dithiazole-5-thione (1.08 g, 7.15 mmol) added thereto, was stirred for 5 hours at room temperature. The reaction, with 1N hydrochloric acid added thereto, was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (3% methanol/chloroform), to give aimed 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 1) (0.883 g, 32%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][N:20]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[N:20]=[CH:21][C:22]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:23][N:24]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ncc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), 2-(4-Methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (70 mg, 0.22 mmol), Pd(PPh3)4 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.22 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 120 min. The crude reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel using MeOH (5% to 10%) in DCM as the eluent to provide the title compound as a pale yellow solid (47 mg, 80%). 1H NMR (400 MHz, CD3OD) δ ppm 10.12 (s, 1H), 8.91 (s, 2H), 8.14 (s, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 3.94 (t, J=4.5 Hz, 4H), 2.56 (t, J=4.9 Hz, 4H), 2.37 (s, 3H); MS ESI 323.1 (100) [M+H]+, calcd for [C17H18N6O+H]+ 323.2.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH2:6]([NH2:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([NH:14][C:1](=[O:5])[CH2:2][OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)CO
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)CO

Procedure:
0.75 mol of glycolic acid were melted at 80° C., then 1.11 mol of octylamine were added dropwise with stirring. After the exothermic reaction had subsided, the mixture was heated for one hour to 165° C. and then the excess amine was distilled off under reduced pressure. The product was obtained after cooling in the form of a white, crystalline solid.
Reaction SMILES: CCO.C1(C)C(S([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:32])[C:19]2[CH:24]=[CH:23][C:22]([NH:25]C(=O)C(F)(F)F)=[CH:21][CH:20]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCOC(C)=O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a stirred EtOH (4 mL) solution containing N-toluenesulfonyl-2-(4-(trifluoroacetylamino)benzoyl)pyrrole (0.500 g, 1.15 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until thin layer chromatography (TLC) analysis showed complete conversion of the starting material. The resulting solution was cooled to room temperature and diluted with EtOAc (20 mL), and the mixture was evaporated to dryness. The crude product was purified by column chromatography (SiO2, EtOAc:Hexanes) to afford the purified product 2-(4-aminobenzoyl)pyrrole (196 mg, 94% yield). 1H NMR (400 MHz, CD2Cl2, 25° C.) 84.19 (bs, 2H), 6.33 (m, 1H), 6.72 (d, 2H), 6.88 (m, 1H), 7.10 (m, 1H), 7.82 (d, 2H), 9.90 (bs, 1H); 13C NMR (100 MHz, CD2Cl2, 25° C.) δ110.9, 114.2, 118.0, 124.5, 128.5, 131.8, 131.9, 151.3, 183.5; HRMS (EI): m/z 186.0793 (100) {M}+.